Heart failure (HF) affects 5,000,000 people in the US alone and is associated with high mortality from sudden arrhythmic death and pump failure. Nearly half of these patients have nonischemic HF, distinct from ischemic HF due to prior myocardial infarction and coronary artery disease. Large animal models of nonischemic HF are necessary to better understand the complex mechanism contributing to nonischemic HF, for development of new therapies, and for translating basic scientific discoveries from bench to bedside. While there are a number of large animal models of nonischemic HF, the canine rapid pacing HF model is one of the most commonly used. It represents the gold standard of large animal models of nonischemic HF and has provided insights into the complex pathophysiology of HF. However, all models have shortcomings, and for the canine pacing HF model these include the reversibility of HF with cessation of pacing (making long-term studies of interventions on the failing heart difficult), decreased collagen content, and the lack of hypertrophy. Recent developments in pharmacologic as well as device-based (CRT, ICD, LVAD), ablative, and cell therapeutic approaches require large animal models that not only resemble human HF (in contractile dysfunction and arrhythmogenicity) but which also (through their stability of a chronic HF state) lend themselves to intermediate- and long-term studies. The goal of this proposal is to develop a novel large animal model of nonischemic HF that is both irreversible and arrhythmogenic. As such this proposal addresses the goals of a recent NIH program announcement that focuses on enhancing translational research from bench to bedside by new animal model development. We have extensive experience with development of a combined volume and pressure overload HF model in the rabbit that is one of the few HF models that is truly arrhythmogenic (with >10% incidence of sudden death) and in which we have demonstrated alterations in intracellular Ca handling, ion channels, adrenergic signaling and gap junctional communication that are similar to human nonischemic HF. We plan to create and validate a comparable large animal model of nonischemic HF in the dog and to test the hypothesis that the hemodynamic burden of combined volume and pressure overload in the canine heart will lead to stable contractile dysfunction and arrhythmogenesis. Specific Aim 1 is to induce and modulate volume and pressure overload to create HF within a time frame of 6-7 months;Specific Aim 2 is to validate this HF model with regards to functional as well as cellular and molecular alterations. Our extensive experience in all aspects of HF development and our intriguing preliminary data attest to the feasibility of the proposed studies. The results of these studies will provide valuable data on a large animal HF model that will assist researchers in understanding the mechanisms of contractile dysfunction and arrhythmogenesis in nonischemic HF, that will nicely complement the canine pacing HF model, that will facilitate chronic translational studies to assess pharmacologic and "human scale" interventions (e.g. CRT, ICDs, LVADs, ablation), and that will lead to new therapeutic approaches for HF patients. PUBLIC HEALTH RELEVANCE: Heart failure (HF) leads to mortality from pump failure and arrhythmias, and large animal models that are irreversible and arrhythmogenic are needed for developing and evaluating new therapeutic approaches. The goal of this proposal is to develop a novel large animal model of HF in the dog (by exposing the heart to volume and pressure overload) as we have successfully done in the rabbit heart. Developing such a novel model will assist researchers in understanding the mechanisms of pump failure and arrhythmias in HF and will help lead to new therapies for heart failure patients.